Regulation of drug delivery through flow diversion

ABSTRACT

The present invention features methods and devices for modulating the rate of delivery of a drug formulation from a drug delivery device by diverting drug away from a drug delivery pathway. In one embodiment, a flow regulator is positioned relative to a drug delivery pathway of a drug delivery system so that adjustment of the flow regulator can provide for diversion of drug away from the drug delivery pathway. Diverted drug can be either delivered into the systemic circulation of the subject, or can be captured in a waste reservoir.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation of PCT application serial no.PCT/US00/28440, filed Oct. 12, 2000, pending, which applicationdesignates the United States; and a continuation-in-part of U.S.application Ser. No. 09/416,379, filed Oct. 12, 1999, pending; each ofwhich applications are incorporated herein by reference in theirentirety.

FIELD OF THE INVENTION

[0002] This invention relates generally to catheters for use in deliveryof drug, particularly in the context of site-specific drug delivery.

BACKGROUND OF THE INVENTION

[0003] Many diseases or indications require long term, chronic deliveryof drugs or agents to a patient, e.g., cancer, arthritis, heart disease,etc. Long term delivery of drugs or agents can be accomplished by use ofdrug delivery systems comprising drug delivery devices which may beimplanted in a patient's body or retained externally. Drug deliverysystems can also deliver drugs or agents to a targeted site within thebody via catheters attached to drug delivery devices with the distal endof such catheters placed at the desired site of delivery in the body,with the catheter acting a conduit for the drug or desired agent fromthe drug delivery device to the desired site of delivery in the body.Drug delivery devices which have adjustable drug delivery rates areknown in the art (see, e.g., U.S. Pat. No. 4,692,147). However, suchdevices with variable or programmable drug delivery rates often includecomplex mechanical elements which may make such drug delivery devicesbulky and subject to failure. Constant drug delivery devices provide fordelivery of drug at a pre-selected, substantially nonfluctuating rate,thus providing for predictability of the dose delivered. However,constant drug delivery devices have the limitation that the rate of drugor agent delivered cannot be readily adjusted, particularly where thedrug delivery device is implanted in the body. The ability to readilyalter the rate at which drug is administered is often desirable in thatit provides flexibility in a therapeutic regimen, and in certain cases,may be a requirement in certain therapies. For example, the drugrequirements of a patient may not be ascertainable prior to thecommencement of a therapy (e.g., dose titration may be required todetermine appropriate dosage), or a patient may require increasing doses(e.g., due to development of tolerance) or decreasing doses (e.g., asthe patient gets well). In a constant drug delivery device, adjustingthe rate of drug delivery can require the removal of the device from thebody of a patient and/or detachment from a drug delivery system (e.g.,detachment from a catheter) and adjustment or even replacement of thedevice.

[0004] There is thus a need in the field for a mechanism which allowsfor adjustment of the rate of a drug delivery device yet obviates theneed for complex or bulky regulatory elements associated with the drugdelivery device. The present invention addresses this problem.

SUMMARY OF THE INVENTION

[0005] The present invention features methods and devices for modulatingthe rate of delivery of a drug formulation from a drug delivery deviceby diverting drug away from a drug delivery pathway. In one embodiment,a flow regulator is positioned relative to a drug delivery pathway of adrug delivery system so that adjustment of the flow regulator canprovide for diversion of drug away from the drug delivery pathway.Diverted drug can be either delivered into the systemic circulation ofthe subject, or can be captured in a waste reservoir.

[0006] In one aspect the invention features a flow regulator comprisinga delivery conduit defining a proximal delivery inlet, a distal deliveryoutlet, and a delivery lumen extending between the proximal deliveryinlet and the distal delivery outlet, the delivery conduit lumendefining a delivery pathway; and a diversion element positioned at thediversion inlet so as to facilitate diversion of flow of drug away fromthe delivery pathway.

[0007] In another embodiment, the flow regulator further comprises adiversion conduit defining a diversion inlet, a diversion outlet, and adiversion lumen extending between the diversion inlet and diversionoutlet, the diversion conduit lumen defining a diversion pathway,wherein the diversion inlet is in fluid communication with the deliveryconduit lumen. In this latter embodiment, drug is diverted from thedelivery pathway and into the diversion pathway defined by the diversionconduit.

[0008] In another embodiment, the diversion element of the flow diverteris actuated manually or remotely when desired by either patient or theclinician so as to regulate the flow of drug in the delivery conduitand, where provided, through the diversion conduit. Remote actuationdevices can comprise programming devices (which can be external to thebody) to adjust programming circuitry associated with the implanteddiversion element or can comprise power sources (which can be externalto the body) which can provide signals to actuate the diversion element.

[0009] In another aspect the invention features a drug delivery systemcomprising a flow regulator and a drug delivery device, and optionally adrug delivery catheter.

[0010] In another aspect the invention features methods foradministering drug to a subject and for controlling an amount of drugadministered to a subject using the flow regulator of the invention.

[0011] A primary object of the invention is to provide a device andmethod for adjustment of the rate at which drug is delivered from a drugdelivery device.

[0012] Another advantage of the invention is that the control of drugdelivery from a drug delivery device to a treatment site is accomplishedwithout the need for adjustment of any element the drug delivery deviceper se, e.g., without adjusting the volume rate of delivery generated bya drug delivery device. This is particularly advantageous where theremay be particular difficulties or inconveniences in adjusting the amountof drug delivered from the drug delivery device.

[0013] Another important advantage of the invention is that the devicesof the invention can be used in a manner that avoids the need to performinvasive procedures to adjust the dose delivered from a drug deliverydevice. For example, the flow regulator can be provided such that thediversion element of the flow regulator remains accessible outside thesubject's body. Alternatively, the diversion element can be remotelycontrollable, thus allowing for adjustment of the implanted flowregulator from outside the body.

[0014] The invention is also advantageous for use where microquantitiesof drug are to be delivered to a treatment site, where the treatmentsite is a relatively confined space, and/or where the drug delivery issite-specific. In these contexts, diversion of even a small volume ofdrug can elicit a proportionately greater effect upon the total volumeof drug delivered to the treatment site and/or the biological effect atthe treatment site.

[0015] Another advantage of the invention is that where the invention isused in connection with delivery of drug to a specific treatment site.The diverted, waste drug can be dumped into the systemic circulation,where the drug is rapidly metabolized, inactivated, and/or eliminatedand thus has no substantial systemic effect upon the subject. Only drugdelivered to a specific treatment site has the desired biologicaleffect. This invention is particularly advantageous where the desiredsite for drug delivery is a site which is relatively isolated fromsystemic clearance effects (e.g., within the pericardial sac of theheart or the intrathecal space of the central nervous system), becausesmall adjustments made to the amount of drugs being delivered to thedesired site can cause significant changes to local concentrations ofthe drug at the site thus the therapeutic effect.

[0016] Where the flow regulator is used with a remote adjustment source,the invention is also advantageous in that provides for control over thetherapy, providing the clinician or the patient the ability to adjustdosing without the need to remove the implant. In addition, a remoteadjustment source that is external to the body is more readilyaccessible for maintenance (e.g., replacement of batteries). Where theexternal remote adjustment source signals the diversion elementperiodically (e.g., only for a length of time necessary to actuate thediversion element), the power requirements are significantly minimized,thus extending the time between maintenance periods (e.g., batterychanges).

[0017] These and other objects, advantages and features of the presentinvention will become apparent to those skilled in the art upon readingthis disclosure in combination with drawings wherein like numerals referto like components throughout.

BRIEF DESCRIPTION OF THE DRAWINGS

[0018]FIGS. 1A, 1B, and 1C are schematics outlining the method of drugdelivery control and use of a flow regulator to accomplish same.

[0019]FIG. 1D is a cut-away view of a solenoid useful as a diversionelement in the flow regulator of the invention.

[0020]FIG. 2 is a cut-away view of a flow regulator 10 comprising arotatable valve 42 with the delivery conduit 20 open.

[0021]FIG. 3 is a cut-away view of a flow regulator 10 comprising arotatable valve 42 with the diversion conduit 30 open.

[0022]FIG. 4 is a cut-away view of a flow regulator 10 comprising a rodelement 52 positioned so that the delivery conduit 20 is open and thediversion conduit 30 is closed.

[0023]FIG. 5 is a cut-away view of a flow regulator 10 comprising a rodelement 52 positioned so that the delivery conduit 20 is closed and thediversion conduit 30 is open.

[0024]FIG. 6 is a cut-away view of a flow regulator 10 comprising a rod52 and toggle switch 54 positioned so that delivery conduit 20 is openand diversion conduit 30 is closed.

[0025]FIG. 7 is a cut-away view of a flow regulator 10 comprising a rod52 and toggle switch 54 positioned so that delivery conduit 20 is closedand the diversion conduit 30 is open.

[0026]FIG. 8 is schematic illustrating regulation of flow rate of adelivery pathway 60 by modulation of relative resistance upon deliverypathway 60 and diversion pathway 70.

[0027]FIG. 9 is a cut-away view of flow regulator 10 comprising ansubstantially uninflated cuff 57 positioned over a deformable distalportion of delivery conduit 20.

[0028]FIG. 10 is a cut-away view of flow regulator 10 comprising aninflated cuff 57 positioned over a deformable distal portion of deliveryconduit 20 to impede flow through delivery pathway 60 and increase flowthrough diversion pathway 70.

[0029]FIGS. 11 and 12 are cut-away views of flow regulator 10 comprisinga hydraulic cuff 57 positioned over a deformable distal portion ofdelivery conduit 20 and over a deformable portion of diversion conduit30.

[0030]FIG. 13 is a cut-away view of flow regulator 10 comprising a rod52 positioned for impinging upon deformable surfaces of delivery conduit20 and diversion conduit 30, with rod 52 in position for substantialclosing of diversion conduit 30.

[0031]FIG. 14 is a cut-away view of flow regulator 10 comprising a rod52 positioned for impinging upon deformable surfaces of delivery conduit20 and diversion conduit 30, with rod 52 in position for substantialclosing of delivery conduit 20.

[0032]FIG. 15 is a cut-away view of a flow regulator 10 in a Y-shapedconfiguration, with valve 31 positioned for diversion of approximately50% of drug into diversion conduit 30.

[0033]FIG. 16 is a cut-away view of a flow regulator 10 in a Y-shapedconfiguration, with valve 31 positioned for substantial closure ofdiversion conduit 30.

[0034]FIG. 17 is a cut-away view of a flow regulator 10 in a Y-shapedconfiguration, with valve 31 positioned for substantial closure ofdelivery conduit 20.

[0035]FIG. 18 is a cut-away view of a flow regulator 10 in a U-shapedconfiguration, with rod-like valve 57 positioned for substantiallycomplete closure of diversion conduit 30 and substantially completeopening of delivery conduit 20.

[0036]FIG. 19 is a cut-away view of a flow regulator 10 in a U-shapedconfiguration, with rod-like valve 57 positioned for substantiallycomplete closure of delivery conduit 20 and complete opening ofdiversion conduit 30.

[0037]FIG. 20 is cut-away view of a flow regulator 10 of the inventioncomprising a waste reservoir 90.

[0038]FIG. 21 is a cut-away view of a flow regulator 10 of the inventionoperably attached to a drug delivery device 110 and to a waste reservoir90.

[0039]FIG. 22 is a cut-away view of a delivery system 100 of theinvention comprising a drug delivery device 110 and a flow regulator 10.

[0040]FIG. 23 is cut-away view of a flow regulator 10 provided as asingle, attachable unit.

[0041]FIG. 24 is a schematic illustrating use of drug delivery system100 implanted for use in site-specific drug delivery to a treatment site7, with diverted drug delivered to a systemic site within the subject'sbody 5.

[0042]FIG. 25 is a cut-away view of a drug delivery system 100comprising a drug delivery device 110 attached to a catheter 120, whichcatheter 120 comprises a flow regulator 10 as an integral component.

DETAILED DESCRIPTION OF THE INVENTION

[0043] Before the present methods and devices are described, it is to beunderstood that this invention is not limited to the particularembodiments described, as such may, of course, vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to limit thescope of the present invention which will be limited only by theappended claims.

[0044] It must be noted that as used herein and in the appended claims,the singular forms “a,” “an,” and “the” include plural referents unlessthe context clearly dictates otherwise. Thus, for example, reference to“a formulation” includes mixtures of different formulations, andreference to “the method of delivery” includes reference to equivalentsteps and methods known to those skilled in the art, and so forth.

[0045] Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimits of that range is also specifically disclosed. Each smaller rangebetween any stated value or intervening value in a stated range and anyother stated or intervening value in that stated range is encompassedwithin the invention. The upper and lower limits of these smaller rangesmay independently be included or excluded in the range, and each rangewhere either, neither or both limits are included in the smaller rangesis also encompassed within the invention, subject to any specificallyexcluded limit in the stated range. Where the stated range includes oneor both of the limits, ranges excluding either or both of those includedlimits are also included in the invention.

[0046] Unless defined otherwise, all technical and scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which this invention belongs. Although any methodsand materials similar or equivalent to those described herein can beused in the practice or testing of the present invention, the preferredmethods and materials are now described. All publications mentionedherein are incorporated herein by reference to disclose and describe thespecific methods and/or materials in connection with which thepublications are cited.

[0047] The publications discussed herein are provided solely for theirdisclosure prior to the filing date of the present application. Nothingherein is to be construed as an admission that the present invention isnot entitled to antedate such publication by virtue of prior invention.Further, the dates of publication provided may be different from theactual publication dates which may need to be independently confirmed.

[0048] Definitions

[0049] “Drug delivery system” is meant to refer to any device orcombination of devices that can provide for transfer of drug from a drugreservoir to a treatment site. “Drug delivery device” thus encompasses,for example, a drug delivery device (e.g., implantable pump) with a flowregulator of the invention; a drug delivery device, flow regulator, anddrug delivery catheter combination; and the like.

[0050] The term “treatment site” as used herein is meant to refer to adesired site for delivery of drug from a drug delivery device of theinvention. “Treatment site” is thus meant to include, although is notnecessarily limited to, a subcutaneous, percutaneous, intravenous,intrathecal, intramuscular, intra-arterial, intravascular,intraperitoneal, intraspinal, epidural, intracranial, peritumoral, orintratumoral (i.e., within a cancerous growth) site within a subject, aswell as sites within or near a selected organ or tissue (e.g., centralnervous system (e.g., intraspinal (e.g., epidural, intrathecal, etc.)within the spinal fluid, brain, etc.), peripheral nervous system,kidney, liver, pancreas, heart (e.g., intrapericardial), lung, eye, ear(e.g., inner ear), lymph nodes, breast, prostate, ovaries, testicles,thyroid, spleen, etc.), digestive system (e.g., stomach,gastrointestinal tract, etc.), skeletal muscle, bone, urinary bladder,gall bladder, adrenal gland, adipose tissue, parathyroid gland, uterus,fallopian tube, skin, into a vessel associated with the circulatorysystem (e.g., artery, arteriole, blood vessel, vein, capillary bed,lymph vessel, particularly arteries that feed a selected organ ortissue)), a tumorous growth (e.g., cancerous tumor (e.g., solid tumor),cyst, etc.), at a site associated with a microbial infection (e.g.,bacterial, viral, parasitic or fungal infection), or to an autologous orsynthetic graft (e.g., a vascular graft).

[0051] The term “access site” or “implantation site” is used to refer toa site on or in a subject at which a catheter of the invention isintroduced for implantation and positioning within the subject's body,e.g., for delivery of drug to a desired treatment site. For example,where a catheter is implanted in a subject for delivery of drug to thespinal cord, the access site or implantation site can be a subcutaneoussite at which a proximal end of the catheter is substantially retained,and the treatment site is a position within or adjacent the spinal cord(treatment site) at which a distal end of the catheter is positioned fordelivery of drug.

[0052] The term “subject” is meant any subject, generally a mammal(e.g., human, canine, feline, equine, bovine, etc.), to which drugdelivery is desired.

[0053] The terms “drug,” “therapeutic agent,” or “active agent” as usedherein are meant to encompass any substance suitable for delivery to atreatment site of a subject, which substances can includepharmaceutically active drugs, as well as biocompatible substances thatdo not exhibit a pharmaceutical activity in and of themselves, but thatprovide for a desired effect at a treatment site, e.g., to flush orirrigate a treatment site (e.g., saline), provide for expression orproduction of a desired gene product (e.g., pro-drug, polynucleotide,and the like), etc. In general, “drug” and the like are used toencompass any drug administered by parenteral administration,particularly by injection (e.g., intravascularly, intramuscularly,subcutaneously, intrathecally, etc.). Drugs compatible for deliveryusing the devices and methods of the invention are discussed below, andare readily apparent to the ordinarily skilled artisan upon reading thedisclosure provided herein. Drugs may optionally be provided incombination with pharmaceutically acceptable carriers and/or otheradditional compositions such as antioxidants, stabilizing agents,permeation enhancers, etc.

[0054] The term “therapeutically effective amount” is meant an amount ofa drug, or a rate of delivery of a drug, effective to facilitate adesired therapeutic effect. The precise desired therapeutic effect willvary according to the condition to be treated, the drug to beadministered, and a variety of other factors that are appreciated bythose of ordinary skill in the art. Determinations of precise dosagesare routine and well within the skill in the art.

[0055] The term “treatment” is used here to cover any treatment of anydisease or condition in a mammal, particularly a human, and includes: a)preventing a disease, condition, or symptom of a disease or conditionfrom occurring in a subject which may be predisposed to the disease buthas not yet been diagnosed as having it; b) inhibiting a disease,condition, or symptom of a disease or condition, e.g., arresting itsdevelopment and/or delaying its onset or manifestation in the patient;and/or c) relieving a disease, condition, or symptom of a disease orcondition, e.g., causing regression of the disease and/or its symptoms.

[0056] Overview

[0057] The present invention encompasses methods and devices forregulating the rate of drug delivery from a drug delivery device. Asillustrated in the schematic of FIGS. 1A-1C, the invention accomplishesregulation of drug delivery rate from a drug delivery device 110 bydiverting the flow of drug away from a primary drug delivery pathway 60(flow direction indicated by arrow 61) and into diversion pathway 70(flow direction exemplified by arrow 71). Diversion of drug away fromthe drug delivery pathway 60 is accomplished using a flow regulator 10.In general, flow regulator 10 comprises: 1) a delivery conduit, whichdefines delivery pathway 60 that flows toward a treatment site duringuse; and 2) a diversion element 40 (represented schematically by a valvesymbol), which may be a valve or other element that facilitatesdiversion of drug flow from the delivery pathway 60, e.g., out of thedelivery conduit through a proximal drug exit outlet positioned alongthe delivery conduit body. In another embodiment, the flow regulatorcomprises a diversion conduit, which is in fluid communication with thedelivery conduit and defines diversion pathway 70 that flows away fromdelivery pathway 60. For clarity, the majority of embodiments of theinvention exemplified herein comprise both a delivery conduit and adiversion conduit; however, the invention is not meant to be so limited.

[0058] The flow regulator can be provided in a variety of embodiments.For example, the diversion element of the flow regulator can bepositioned at the juncture of the delivery and diversion pathways (see,e.g., FIG. 1A), at a site of the delivery pathway distal to thediversion outlet (see, e.g., FIG. 1B), or, where the flow regulatorcomprises a diversion conduit that defines the diversion pathway, thediversion element can be positioned along the body of the diversionconduit (see, e.g., FIG. 1C).

[0059] In one embodiment, the diverted drug is collected in a wastereservoir. This embodiment is particularly useful where the drugdelivery system is for systemic drug delivery, i.e., the rate ofsystemic drug delivery can be regulated by diverting the drug into awaste reservoir.

[0060] In another embodiment, drug diverted into the diversion pathway70 can be delivered to a site within the subject where the drug willhave few or no undesirable side effects, e.g., to a site in the bodyaway from the site of action of a drug. This embodiment of the inventionis particularly useful where there is a local advantage to delivery ofdrug to a target site, which local advantage can be due to, for example,delivery of drug to directly to the desired site of action (e.g., toavoid side effects associated with systemic delivery), concentrationeffects (e.g., site-specific delivery provides for a drug concentrationat the treatment site that is difficult or undesirable to accomplishthrough systemic delivery routes), and/or characteristics of the drugitself (e.g., short half-life, inactivation in the systemic circulation,etc.). This embodiment of the invention provides an elegant means forregulating drug delivery rate by taking advantage of the difference inthe amount of drug that elicits a biological effect at a specific siterelative to an amount of drug that elicits a biological effect whendelivered systemically. The invention takes advantage of this differencein relative therapeutic thresholds to use the systemic circulation as a“waste reservoir” for drug diverted from a drug delivery pathway thattargets a specific treatment site.

[0061] In another embodiment, the diversion element of the flowregulator is actuated by a remote actuating device. The remote actuationdevice can signal the diversion element to open completely to the drugdelivery pathway, open completely to a diversion pathway, or to providefor adjustment of the diversion element at any position in between theseextremes to allow for adjustment of drug flow to the treatment site. Theremote actuation device can also be used to actuate the diversionelement intermittently to provide for, for example, variable switchingbetween the opening and closing of the delivery pathway, e.g., thediversion element can cause drug to be delivered into the deliverypathway for a selected period of time at specified intervals dependingon factors such as the half-life of the drug at the delivery site, e.g.,drug can be delivered into the delivery pathway for 1 hour followed by 3hours where the drug flow will be diverted to the diversion pathway.

[0062] Specific exemplary embodiments of the invention are describedbelow in more detail. The embodiments described below and in the figuresare only exemplary and are not meant to be limiting in any way.

[0063] Exemplary Flow Regulator Embodiments

[0064] The flow regulator of the invention can comprise any elementsuitable for facilitating a degree of opening and closing of the drugdiversion pathway and/or for redirecting a portion of the drug flow indelivery pathway into the diversion pathway. Diversion elements suitablefor use in a flow regulator of the invention include, but are notnecessarily limited to, any of a variety of remotely controllable ormanually actuated valves, piezoelectric valves, solenoids, and switches,as well as any of a variety of devices that can provide for varyingrelative resistance to flow through the drug delivery pathway and thedrug diversion pathway of the drug delivery system. In one embodiment,the diversion element of the flow diverter is actuated remotely by aremote actuation device external to the body when desired by eitherpatient or the clinician so as to regulate the flow of drug in thedelivery conduit and, where provided, through the diversion conduit. Forexample, in one embodiment, the diversion element 40 is a valve, which,as exemplified in FIG. 1D, can be in the form of a solenoid 47. Any of avariety of solenoids, which are well known in the art, are suitable foruse as valves in the diversion element. For example, the diversionelement can be a valve in the form of a solenoid. The solenoid can bepositioned for opening and closing of a proximal drug exit outlet of adelivery conduit, for opening and closing of the delivery conduit lumen(e.g., thereby increasing flow through a proximal drug exit outlet of adelivery conduit), or within a diversion conduit.

[0065] Various solenoids suitable for use in the invention are wellknown in the art. As exemplified in FIG. 1D solenoid 47 can comprise arod or piston 52 which is slidably received within shaft 53. Seals 47provide a fluid-tight seal to inhibit backflow into the solenoidmechanism. FIG. 1D depicts the solenoid positioned for opening andclosing of a conduit lumen, e.g., positioned within the body 24, 34 of adelivery conduit 20 or of a diversion conduit 30 to facilitate varyingdegrees of opening and closing of the delivery conduit lumen 24 ordiversion conduit lumen 34. When the solenoid 47 is in the openposition, rod 52 is completely or partially withdrawn into shaft 53 toallow flow through lumen 24, 34. When the solenoid 47 is in the fullyclosed position, rod 52 is received within abutment 48, providing afluid seal between rod 52 distal end 51 and the abutment 48. Supplyingpower to electrical coils 49 surrounding rod 52 causes movement of rod52 within shaft 53 to facilitate varying degrees of opening and closingof the lumen or other opening.

[0066] In another embodiment, illustrated in FIGS. 2 and 3, flowregulator 10 comprises a diversion element in the form of rotatablevalve 42 comprising a substantially T-shaped conduit 43 seated within aring-like structure 44. The rotatable valve is positioned in a drugdelivery conduit 20 and a drug diversion conduit 30. Drug deliveryconduit 20 comprises a substantially elongate member defining a lumenthrough which drug delivery pathway 60 travels from a proximal druginlet opening 21 to a distal drug delivery outlet opening 22 when thevalve 42 is in a position as illustrated in FIG. 2. Drug diversionconduit 30 comprises a substantially elongate member defining adiversion inlet 31 and a diversion outlet 32, and further defining alumen through which a drug diversion pathway 70 travels when the valve42 is in a position as illustrated in FIG. 3. Delivery conduit 20 anddiversion conduit 30 can be provided as separate, attached components,or molded as a single piece (e.g., the diversion conduit can be anextended orifice from a side wall of the delivery conduit). The valve 42and at least portions of drug delivery conduit 20 and diversion conduit30 are mounted within a housing element 45 to maintain the lumen ofconduits 20, 30, and 43 within substantially the same plane and tooptionally provide a liquid tight or liquid resistant compartment forthe flow regulator 40, e.g., to prevent flow of environmental fluid intothe openings of the valve conduit 43. Housing element 45 may compriseelements to facilitate positioning of flow regulator valve 40 and/or toensure that rotation of valve 40 is stopped at a position that providesfor fluid communication between drug inlet opening 21, through valve 40and out either distal outlet 22 (FIG. 2) or diversion outlet 32 (FIG.3). Seals 47 positioned around the outer circumference of rotating valve40 and/or at the openings of the drug delivery conduit 20, drugdiversion conduit 30, and at a position within housing element 45 toensure closure of an end of T-shaped conduit 43 that is not incommunication with either delivery conduit 20 or diversion conduit 30during use (see, e.g., FIGS. 2 and 3) provide for a liquid-tight seal tofacilitate flow through the valve conduits. The rotatable valve 42 ofthe flow regulator can be manually or remotely actuated, and can berotated using mechanical, electromechanical (e.g., a microdrive engine),or electromagnetic (e.g., a solenoid) means.

[0067] In another embodiment, the flow regulator 10 comprises diversionelement in the form of a slidable rod element 52 in a gearshift-typevalve mechanism (see, e.g., FIGS. 4 and 5). The ends of the rod 52 areslidably received within side openings of the diversion conduit 30 andof the drug delivery conduit 20. Seals 47 at each of these openingsprovide a liquid-tight seal with rod 52. FIG. 4 shows rod 52 positionedsuch that drug delivery conduit 20 is completely open and diversionconduit 30 is completely closed, e.g., all drug formulation introducedat inlet 21 flows through drug delivery pathway 60 to drug outlet 22.Sliding of rod 52 into the lumen of drug delivery conduit 20 canproviding for varying and inversely proportional degrees of closing ofdrug delivery conduit 20 and opening of diversion conduit 30, up to andincluding complete closure of drug delivery conduit 20 and completeopening of diversion conduit 30 such that substantially all drugintroduced into inlet 20 flows through diversion pathway 70. The flowregulator can be housed within a housing element 45 to protect themechanics of the flow regulator from environmental fluids. Movement ofrod 52 can be accomplished manually or remotely actuated, and can berotated using mechanical, electromechanical (e.g., a microdrive engine),or electromagnetic (e.g., a solenoid) means.

[0068] In another embodiment, flow regulator 10 comprises a diversionelement comprising a rod element 52 and a toggle switch 54 containedwithin housing element 45 (FIGS. 6 and 7). As in the exemplaryembodiments illustrated in FIGS. 4 and 5, rod 52 is slidably receivedwithin a side opening of the diversion conduit 30 and a side opening ofthe drug delivery conduit 20, with seals 47 at each of these openingsproviding a liquid-tight seal with rod 52. Toggle switch 54 is attachedto rod 52, and hinged within housing element 45 at pivot point 55 androd 52 at pivot point 56. Movement of toggle switch 54 in a directiontoward delivery conduit 20 results in simultaneous opening of deliveryconduit 20 and closing of diversion conduit 30; movement of toggleswitch 54 in a direction toward the diversion conduit 30 results insimultaneous closing of delivery conduit 20 and opening of diversionconduit 30. The toggle switch 54 and rod 52 can be adjusted to providefor any relative degree of opening and closing of the conduits 20 and30. Movement of toggle switch 55 and rod 52 can be accomplished manuallyor remotely actuated, and can be rotated using mechanical,electromechanical (e.g., a gear drive engine), or electromagnetic (e.g.,a solenoid) means.

[0069] In another embodiment, flow diversion is accomplished bydeformation of the diversion conduit 30 and/or delivery conduit 20 tovary their relative inner diameters. As illustrated schematically inFIG. 8, increasing the resistance on delivery path 60 (e.g., at point A)relative to the resistance on diversion pathway 70 (e.g., at point B)will result in diversion of drug into diversion pathway 70, e.g., out aproximal drug exit outlet 25 which may be in fluid communication with adiversion conduit 30 (represented by dashed lines in FIG. 8). Likewise,increasing the resistance on diversion path 70 relative to theresistance on delivery pathway 60 will result in less drug flowingthrough diversion pathway 70 and more flowing through delivery pathway60. Resistance at diversion pathway 70 and/or delivery pathway 60 can beprovided by application of external pressure which can be provided bymechanical force, hydraulic pressure and the like to impinge against adeformable conduit wall portion and/or to pinch the conduit closed.

[0070] A starting delivery conduit flow rate greater than a diversionconduit flow rate can be established in order to prevent drug fromsimply flowing through the diversion pathway with little or no drugreaching delivery outlet at the delivery conduit distal end. Forexample, the delivery conduit inner diameter can be greater than thediversion conduit inner diameter, thus providing for a slower flow ratethrough the diversion conduit. Alternatively or in addition, theproximal drug exit outlet of the delivery conduit can be of a smalldiameter which allows only a “slow drip” through the proximal drug exitoutlet unless flow resistance is increased in the delivery conduit at asite distal to the drug exit outlet. Alternatively or in addition, thediversion conduit inner diameter can be of a smaller diameter relativeto the delivery conduit inner diameter, allowing only a slow drip intothe diversion conduit in the absence of external pressure on thedelivery conduit. Alternatively or in addition, the proximal drug exitoutlet and/or diversion conduit can be completely or partially filledwith a porous or semi-porous material to increase flow resistance in thediversion conduit relative to the delivery conduit.

[0071] Modulating the relative flow resistance of the delivery pathway60 relative to the diversion pathway 70 can be accomplished in a varietyof ways. For example, the diversion element of the flow regulator cancomprise a compression element that provides a means for alternatelydecreasing and increasing the inner diameter of the delivery conduit, ofthe diversion conduit, or both. In one embodiment exemplified in FIGS. 9and 10, flow regulator 10 comprises a diversion element in the form of acompression element, where the compression element is an inflatable cuff57 positioned over a deformable distal portion of delivery conduit 20.Cuff 57 can be inflated using a balloon-like inflating element 58, whichcomprises a balloon, a connector that communicates the balloon with thecuff, and a one-way valve positioned between the balloon and the cuff.When substantially uninflated, cuff 57 does not cause any substantialdeformation of delivery conduit 20. Depression of the balloon 58 resultsin inflation of cuff 57, which in turn results in deformation ofdelivery conduit 20 beneath cuff 57 and restriction of flow of drugthrough delivery pathway 60, thus increasing flow through diversionpathway 70.

[0072] In another embodiment, the relative flow resistance in deliveryconduit 20 and diversion conduit 30 is controlled using a hydraulic cuff80, which comprises balloon elements 81 and 82 positioned over adeformable distal portion of delivery conduit 20 and over a deformableportion of diversion conduit 30, respectively. The hydraulic cuff 80comprises a rod 52 that is slidably positioned within shaft 53. Movementof rod 52 within shaft 53 in a direction toward diversion conduit 30increases pressure on gas or fluid in balloon element 82, and aconcomitant decrease in pressure on gas or fluid in balloon element 81,resulting in relatively increased flow through delivery conduit 20 andrelatively decreased flow through diversion conduit 30 (FIG. 11).Movement of rod 52 within shaft 53 in a direction toward deliveryconduit 20 increases pressure on gas or fluid in balloon element 81, anda concomitant decrease in pressure on gas or fluid in balloon element82, resulting in relatively increased flow through diversion conduit 30and relatively decreased flow through delivery conduit 20 (FIG. 12).

[0073] In another embodiment exemplified in FIGS. 13 and 14, thediversion element of flow regulator 10 is a compression elementcomprising a rod element 52 slidably positioned within shaft 53 so as tobe in alternate or simultaneous contact with a deformable portion ofdiversion conduit 30 and a deformable portion of delivery conduit 20distal to the diversion conduit 30. Flow regulator 10 is contained withhousing 45, which housing can provide for a fluid-resistant seal toinhibit entry of environmental fluids into the flow regulator mechanism.Abutment walls 85 are positioned adjacent delivery conduit 20 anddiversion conduit 20 at a wall opposite the deformable wall to becontacted by rod 52. Abutment walls 85 provide resistance to thepressure generated by rod 52 when impinging upon the opposite conduitwall to deform the conduit and modulate the conduit inner diameter,e.g., to facilitate deformation of the conduit wall in contact with rod52 rather than movement of the entire conduit. Movement of rod 52 withinshaft 53 in a direction toward diversion conduit 30 results indeformation of a deformable portion of diversion conduit 30, resultingin complete or partial pinching of the deformable portion of diversionconduit 30 (see, e.g., FIG. 13) with simultaneous opening of deliveryconduit 20. Movement of rod 52 in a direction toward delivery conduit 20results in deformation of a deformable portion of delivery conduit 20,resulting in complete or partial pinching of the deformable portion ofdelivery conduit 20 with simultaneous opening of diversion conduit 30(see, e.g., FIG. 14). Rod 52 can be positioned to provide any of avariety of gradations of relative opening and closing of deliveryconduit 20 and diversion conduit 30. Movement of rod 52 can beaccomplished manually or remotely actuated, and can be rotated usingmechanical, electromechanical (e.g., a microdrive engine), orelectromagnetic (e.g., a solenoid) means. In a similar embodiment, rod52 is provided in association with a toggle switch that facilitatesmovement of rod 52, similar to the embodiment described above and inFIGS. 6 and 7.

[0074] Conduit configuration

[0075] While the above exemplary embodiments have illustrated the flowregulators comprising both a delivery conduit and diversion conduit ascomprising a T-shaped intersection between a delivery conduit and adiversion conduit, other embodiments are contemplated by the invention.As exemplified in FIGS. 15-17, a proximal portion of delivery conduit 20a extends from a drug inlet 21 to a Y-shaped branch point at which theconduit diverges to provide a diversion conduit 30 and a distal portionof the delivery conduit 20 b. Flow regulator 10 comprises a flap valve87 positioned at the conduit branch point, which flap valve 87 pivots ata point within the conduit branch point to provide for relative openingand closing of delivery conduit 20 b and diversion conduit 30. FIG. 15illustrates positioning of flap valve 87 so as to divert approximatelyhalf of the flow of drug from drug inlet 21 into delivery conduit 20 band half into diversion conduit 30. FIGS. 16 and 17 illustrate flapvalve 87 positioned for substantially complete closure of diversionconduit 30 (FIG. 16) and substantially complete closure of deliveryconduit 20 b (FIG. 17).

[0076] In another embodiment, flow regulator 10 comprises a tuning-forkor U-shaped configuration (see, e.g., FIGS. 18 and 19). In thisembodiment a proximal portion of delivery conduit 20 a and intersects ata connector conduit 88 which in turn is in communication with a distaldelivery conduit portion 20 b and with diversion conduit 30. A rod 52 isslidably received within shaft 53 and within openings in distal deliveryconduit 20 and diversion conduit 30. Seals 47 positioned around theconduit openings provide for a liquid tight or liquid resistant seal toprevent leaking of drug from the conduits. Sliding of rod 52 towarddiversion conduit 30 results in closing of diversion conduit 30 andsimultaneous opening of distal delivery conduit 20 to allow flow throughdelivery pathway 60. Sliding of rod 52 toward distal delivery conduit 20b results in closing of distal delivery conduit 20 b and simultaneousopening of diversion conduit 30 to allow flow of drug through diversionpathway 70. Rod 52 can be moved through mechanical, electromechanical,or electromagnetic means, and can be activated manually or remotely. Forexample, rod 52 can be a solenoid or a piston-like element.

[0077] Waste reservoir embodiments

[0078] In all embodiments described herein and contemplated by theinvention, drug that flows through the proximal drug exit outlet of thedelivery conduit can be optionally collected in a waste reservoir.Embodiments with waste reservoirs are particularly useful when the flowregulator is used as part of a drug delivery system wherein drug isadministered systemically instead of locally. In general, the wastereservoir is a bag, pouch, container, receptacle, bellows (e.g., metalbellows) or other receiving element in fluid communication with thediversion conduit outlet and/or delivery conduit proximal drug exitoutlet. The waste reservoir can be provided as an extension of thecatheter body, or can be provided as a separate component that is eitherremovably or permanently attached. Where the waste reservoir is to bepositioned within the subject's body during use, it is preferablypermanently attached and comprises an implantable, biocompatiblematerial.

[0079] The waste reservoir can be of any size or shape suitable for usewith the delivery exit catheter with which it is to be used. Forexample, the waste reservoir can be provided as a separate, closed lumenwithin the wall of the diversion conduit, the delivery conduit, orwithin a wall of a catheter used in connection with the flow regulator.Alternatively, the waste reservoir can be provided within a housingelement of the flow regulator or within a chamber of a drug deliverydevice used in connection with the flow regulator of the invention. Thewaste reservoir can comprise any suitable, substantiallydrug-impermeable material (e.g., multilaminate impermeablepolymers/metalized polymer or metal/plastic laminate), and preferablydoes not react in an unintended manner with the active agentformulation. The waste reservoir can be designed to facilitate removalof drug it contains, e.g., by means of a self-sealing septum that allowsneedle access.

[0080] In one embodiment of particular interest, the waste reservoir isprovided as part of the delivery pump such that on removal of the pumpfrom the drug delivery system (e.g., detachment of the pump from a drugdelivery catheter) the reservoir is automatically removed. The wastereservoir can also be co-located with the pump or molded within the pumpbody.

[0081] In one embodiment, exemplified in FIG. 20, the waste reservoir 90is provided as a component of flow regulator 10. The proximal end of thedelivery conduit can be adapted for receiving a drug delivery device,exemplified in FIG. 20 as device receiving chamber 98. The wastereservoir 90 of FIG. 20 comprises a waster receiving chamber 91. Aswasted is delivered into waste receiving chamber 91, piston 92 isadvanced in a direction toward vent hole 93, which allows fordisplacement of fluid or gas contained within the proximal portion ofwaste reservoir 90. Where the waste reservoir is provided as adetachable component, the waste reservoir can be removed when descried,e.g., when the waste reservoir is f all such that piston 92 has reachedthe waste reservoir proximal end. In another embodiment, exemplified inFIG. 21, waste is received within an expandable bellows 94.

[0082] Flow regulator as element of drug delivery system

[0083] The flow regulator of the invention can be provided as anintegral or detachable element of a drug delivery system component. Forexample, the flow regulator and optional waste reservoir can be anintegral or detachable portion of a drug delivery device. For example,FIG. 22 illustrates a drug delivery system 100 comprising a drugdelivery device 110 and a flow regulator 40, which drug delivery system100 can further comprise a drug delivery catheter 120. In thisembodiment, flow regulator 10 is permanently attached to (e.g., viawelding, adhesive bonding, etc.) or an integral component of drugdelivery device 110.

[0084] The drug delivery device minimally comprises a drug releasedevice (e.g., a constant rate drug delivery device, such as an osmoticpump) having a proximal end and a distal end, which distal end defines adrug delivery orifice. The distal end of the drug delivery device isattached to a proximal end of the catheter so that the drug flow pathwayfrom the drug delivery device reservoir continues through the drugdelivery device orifice and into the delivery conduit of the flowregulator. The present invention finds particular use with those drugrelease devices that provide for delivery of drug at a pre-selected ratethat cannot be readily adjusted, but can be used with any of a widevariety of drug delivery devices including, but not limited to,diffusion-based delivery system (e.g., erosion-based delivery systems(e.g., polymer-impregnated with drug placed within a drug-impermeablereservoir in communication with the drug delivery conduit of thecatheter of the invention), electrodiffusion systems, and the like) andconvective drug delivery systems (e.g., systems based uponelectroosmosis, vapor pressure pumps, electrolytic pumps, effervescentpumps, piezoelectric pumps, osmotic pumps, etc.). Drug release devicesbased upon a mechanical or electromechanical infusion pump, may also besuitable for use with the present invention. Examples of such devicesinclude those described in, for example, U.S. Pat. Nos. 4,692,147;4,360,019; 4,487,603; 4,360,019; 4,725,852, and the like. In general,the present invention can be used in conjunction with refillable,non-exchangeable pump systems that are normally used to deliver asubstance through a relatively impermeable catheter.

[0085] In a preferred embodiment, the drug release device is anosmotically-driven device. Exemplary osmotically-driven devices suitablefor use in the invention include, but are not necessarily limited to,those described in U.S. Pat. Nos. 3,760,984; 3,845,770; 3,916,899;3,923,426; 3,987,790; 3,995,631; 3,916,899; 4,016,880; 4,036,228;4,111,202; 4,111,203; 4,203,440; 4,203,442; 4,210,139; 4,327,725;4,627,850; 4,865,845; 5,057,318; 5,059,423; 5,112,614; 5,137,727;5,234,692; 5,234,693; 5,728,396; and the like. In one embodiment, thedrug release device is an osmotic pump, more particularly an osmoticpump similar to that described in U.S. Pat. No. 5,728,396, e.g., a DUROS

osmotic pump.

[0086] The drug delivery system 100 can further comprise a drug deliverycatheter 120, which can be attached to drug delivery device 110 and flowregulator 40 via an attachment element 130 provided at a distal end ofdelivery conduit 20 of flow regulator 40. The attachment elementfacilitates permanent or reversible attachment of the catheter to thedrug delivery device and/or stabilizes such attachment, e.g.,substantially diminish movement of the catheter away from the drugdelivery device (e.g., to provide strain relief), so as to reduce riskof breakage of the catheter at the attachment site. The attachmentelement can be provided as a portion of or component associated with thecatheter proximal end, flow regulator delivery conduit, a combination ofboth, or as a separate element. Any of a variety of attachment elementsare suitable for use including, but not limited to, a press fit lock,threaded connector elements, luer lock elements, bayonet connectors,etc.

[0087] Flow regulator as element of a drug delivery catheter

[0088] In one embodiment, the flow regulator is provided as an elementof a drug delivery catheter, which catheter is attachable to a drugdelivery device. In general, the catheter comprises: 1) a catheter bodycomprising a proximal end defining a drug inlet, a distal end defining adrug delivery outlet, and a lumen extending between the proximal anddistal ends and defining a drug delivery pathway; and 2) a flowregulator for control of drug flow from the drug delivery pathway andinto a diversion pathway.

[0089] For example, flow regulator can be provided as a component of adrug delivery catheter. In this embodiment, delivery conduit of the flowregulator is positioned within and attached to the body of the catheterin a liquid-tight manner or the delivery conduit and catheter lumen canbe formed from a single, continuous element (e.g., are molded orextruded as a single element). The catheter proximal end can be adaptedfor attachment to drug delivery device as described above.

[0090] The catheter body can be any suitable shape including, but notlimited to, tubular, elliptical, cylindrical, etc., and may be eithersmooth on the catheter outer surface, or may comprise ridges (e.g.,longitudinal, axial, or circumferential) or other surface variations aswill be desirable for the specific applications for which the catheteris used. The catheter body comprises a biocompatible material, morepreferably an implantable grade biocompatible material. Exemplarymaterials include, but are not necessarily limited to, biocompatiblepolymers, elastomers, metals, metal alloys, glasses, laminates ofhydrophilic polymers and hydrophobic polymers, multilaminates orpolymer, metals, and/or glasses; and the like.

[0091] In general, the catheter and flow regulator can be of anysuitable dimension, which can be varied according to the delivery siteand other factors. For example, the outer diameter of the catheter bodyis generally from about 0.01″ (about 0.25 mm) to about 0.200″ (about 5mm). The inner diameter of the catheter and of the flow regulatordelivery conduit can also be varied as needed, and can range from, forexample, about 0.0002″ (about 0.005 mm) to about 0.025″ (about 5 mm).

[0092] The dimensions of the catheter (e.g., inner diameter, outerdiameter, wall thickness, etc.) can be substantially the same throughoutthe length of the catheter, or can be varied. For example, the catheterbody can be tapered at the distal end relative to the proximal end,e.g., to facilitate implantation into small and/or delicate structuresin the subject and/or to provide a wider proximal end for receiving adrug delivery device. The catheter can comprise a single delivery outletor a plurality of such delivery outlets. Furthermore, the amount of drugthat moves through the multiple delivery outlets can be controlled byone or more flow regulators. Catheters comprising multiple drug deliveryoutlets can be used to facilitate delivery of drug to multiple treatmentsites, and may further be branched to provide for delivery to multiple,specific treatment sites. The catheter can comprise additional elements,such as radiopaque markers to facilitate implantation, a valve at thecatheter distal end (e.g., a duckbill valve), a filter positioned withinthe catheter lumen, etc.

[0093] Flow regulator as separate unit

[0094] In another embodiment, flow regulator 10 is provided as aseparate element that is adapted for attachment to a drug deliverydevice and, optionally, a drug delivery catheter. In one exampleillustrated in FIG. 23, flow regulator 10 is provided within housing 45.Drug inlet 21 of delivery conduit 20 is adapted to receive a distalportion of a drug delivery device 110 to provide for flow of drug fromthe drug delivery device into delivery conduit 20. One or more seals 47can be positioned within delivery conduit 20 or on an external surfaceof drug delivery device 110 to facilitate holding drug delivery device110 in place and/or to provide a liquid-tight seal. Housing 45 cancomprise an attachment element (exemplified by a press fit lock in FIG.23) to facilitate retention of drug delivery device 110 in housing 45.Delivery conduit distal end 22 can be adapted to receive a drug deliverycatheter to provide for flow of drug from delivery conduit 22 and into alumen of the drug delivery catheter. Diversion element 40 of flowregulator 10 is contained with housing 45, with diversion conduit 30optionally attached to waste reservoir 90. Alternatively, the flowregulator may be adapted to allow for flow of diverted drug directlyinto a waste reservoir, e.g., without a diversion conduit. Allcomponents of flow regulator 10 can be contained within housing 45, asexemplified in FIG. 23, to provide all elements of flow regulator 10 ina single unit. In this embodiment, flow regulator 10 can be provided asa disposable, exchangeable unit that can be adapted for use with avariety of drug delivery devices and drug delivery catheters.

[0095] During use, drug flows through delivery pathway 60 from drugreservoir 113 into drug inlet 21, through delivery conduit 20 and, whereused, into drug delivery catheter 120 and out catheter distal outlet 122to a treatment site. Activation of the diversion element 40 of flowregulator 10 results in diversion of drug from delivery pathway 60 andinto diversion pathway 70. Where the flow regulator comprises adiversion conduit, diverted drug flows through a diversion pathwaydefined by the diversion conduit. Optionally, diverted drug can becollected in waste reservoir 90. The dimensions of the flow regulator(e.g., inner diameter of delivery and diversion conduits, dimensions ofhousing element, etc.) can be varied according to the various drugdelivery device and catheters used with the flow regulator, as well aswith the application for which the flow regulator is to be used.

[0096] Flow regulator with remote actuation device

[0097] In one embodiment, the diversion element of the flow regulator isactuated by a remote actuation device which can be used by a patient orclinician to adjust the amount of drug delivered to the treatment site.As used herein “remote actuation device” indicates that actuation deviceseparate from the flow regulator, and may be external to the patient'sbody, implanted, or partially implanted, preferably external to thepatient's body. Actuating the diversion element from a remote actuationdevice provides for advantage in patient therapy including, but notnecessarily limited to, direct patient or clinical control over thetherapy received without the need for adjustment of the implanted flowregulator or pump, and flexibility in adjustment of the dose beingdelivered. In addition, the remote actuation device can provide forclinical pre-set upper limits of possible dosage, lower limits ofpossible dosage, or both by inputting such limits in the ability of theremote actuation device to actuate the diversion element, thusdiminishing the likelihood of improper dosing. In addition, patienttherapy can be altered by replacing and adjusting the remote actuationdevice and its components rather than adjusting the implanted flowregulator or other drug delivery device component.

[0098] The remote actuation device can be used so that it signals thediversion element periodically, and only for a length of time necessaryto actuate the diversion element. When used in this manner, the powerrequirements of the remote actuation device are minimized, and can serveto minimize maintenance (e.g., minimize battery replacements). Ingeneral, the period between signaling events is determined by severalfactors, including, but not necessarily limited to, the half-life of thedrug to be delivered, the amount of drug desired to be delivered alongthe delivery pathway of the flow regulator (e.g., relative to the amountto be diverted through the diversion pathway), and other factors thatwill be readily apparent to the ordinarily skilled artisan upon readingthe present disclosure.

[0099] Remote actuation devices can operate in a variety of ways. Forexample, the flow regulator may comprise programming circuitry whichcontrols the diversion element, and the remote actuation device cantransmit signals, by radio frequency telemetry for example, to theprogramming circuitry to actuate the diversion element. Exemplary remoteprogrammers based upon RF signals used to actuate implanted drugdelivery pumps are described in, for example, U.S. Pat. No. 5,443,486and 5,820,589, and such mechanisms can be adapted for use in the presentinvention by those of skill in the art.

[0100] In other embodiments, the remote actuation device comprises apower source that will transmit energy to actuate the diversion element.In such embodiments, because the power source used to actuate thediversion element is separate from the flow regulator, the flowregulator can be much smaller in size, which is particularlyadvantageous when the flow regulator is to be implanted. In oneembodiment, the power source on the remote actuation device is operatedonly for a period of time during which drug delivery is desired, whereremoval of the external power source results in substantially nodelivery of drug to the treatment site (e.g., the delivery pathway isclosed upon removal of the external power source from operation). Inanother embodiment, the external power source is operated to provide foradjustment of the diversion element, leaving the diversion element in adesired position to allow for a desired flow rate of drug through thedelivery pathway. Remote power sources capable of delivery of power toactuate implanted devices are known in the art, for example inconnection with implantable tissue stimulators such as the MedtronicItrel II, Model 7424, transcutaneous tissue stimulators such as theMedtronic Xtrel, Model 3470, and such mechanisms can be adapted to beused in this invention by those of skill in the art.

[0101] Drugs for delivery using the drug delivery system of theinvention

[0102] Any of a wide variety of drugs can be delivered using the drugdelivery system of the invention. Drugs suitable for delivery arepreferably provided as flowable formulations, and are generally providedas liquids, gels, pastes, or semisolids. The drugs may be anhydrous oraqueous solutions, suspensions or complexes, and may be formulated withpharmaceutically acceptable vehicles or carriers, as well as additionalinert or active ingredients. The drugs of formulations suitable fordelivery using the invention may be in various forms, such as unchargedmolecules, components of molecular complexes or pharmacologicallyacceptable salts. Also, simple derivatives of the agents (such asprodrugs, ethers, esters, amides, etc.) that are easily hydrolyzed bybody pH, enzymes, etc., can be employed. Preferably the agents areformulated so as to remain stable for long periods of storage on theshelf or under refrigeration, as well as for long periods stored in animplanted drug delivery system of the invention.

[0103] Of particular interest is the treatment of diseases or conditionsthat require long-term therapy, e.g., chronic and/or persistent diseasesor conditions for which therapy involves treatment over a period ofseveral days (e.g., about 3 days to 10 days), to several weeks (e.g.,about 3 or 4 weeks to 6 weeks), to several months or years, up toincluding the remaining lifetime of the subject. Subjects who are notpresently suffering from a disease or condition, but who are susceptibleto such may also benefit from prophylactic therapies using the devicesand methods of the invention.

[0104] Use of the Flow Regulator in Drug Delivery

[0105] The drug delivery system of the invention can be implanted at anyconvenient site within the subject's body using methods and tools wellknown in the art, and can be oriented for delivery to any desiredtreatment site. The devices of the present invention are preferablyrendered sterile prior to implantation, which can be accomplished byseparately sterilizing each component, e.g., by gamma radiation, steamsterilization or sterile filtration, etc., then aseptically assemblingthe final system, or by first assembling the system then sterilizing thesystem using any appropriate method. The final sterilized device may beprovided in a package to retain its sterility.

[0106] In one embodiment, the drug delivery system of the invention ispartially or completely implanted, with at least portion of the drugdelivery device retained at an accessible, external or subcutaneous sitewithin the subject's body (e.g., under the skin of the arm, shoulder,neck, back, or leg) or within a body cavity (e.g., within the mouth).

[0107] The relative position of the flow regulator can be varied withrespect to the subject's body. For example, the portion of the cathetercomprising the flow regulator can be maintained at a site external tothe subject's body to allow for ready adjustment of the flow regulator,e.g., where the flow regulator comprises a manually adjustable diversionelement. Where all or a portion of the flow regulator is maintained atan external site, it may be desirable that the drug delivery systemfurther comprise a waste reservoir for collection of drug that flowsthrough the diversion pathway. In general, a drug delivery outlet (i.e.,the delivery outlet or the flow regulator, a drug delivery catheterassociated with a flow regulator, or both) is implanted within a subjectfor delivery of drug to a treatment site.

[0108] In one embodiment exemplified in FIG. 24, a drug delivery outlet22 is implanted for site-specific drug delivery to a selected treatmentsite (e.g., within the central nervous system (e.g., an intraspinal site(e.g., an epidural or intrathecal site, site within the brain, etc.)),and the diversion outlet 32 positioned within the body at a site outsidethe specific treatment site(e.g., at a subcutaneous site or other siteexternal to the specific treatment site that provides for systemicdelivery of the diverted waste drug). In this embodiment, drug thatflows out the drug delivery outlet 22 is delivered to the selectedspecific treatment site 7 (e.g., to the spine), while drug that flowsout the diversion outlet 32 is delivered systemically in the subject'sbody 5, where the drug can be safely diluted in the systemiccirculation. In an alternative embodiment, diverted drug flows out thedelivery conduit proximal drug exit outlet and directly into thesystemic circulation, e.g., without flowing through a diversion conduit.

[0109] Embodiments that involve delivery of diverted drug to thesystemic circulation are particularly attractive where microquantitiesof drug (e.g., on the order of micrograms per day) are delivered to thespecific treatment site, and thus the amount of drug diverted into thediversion conduit and to a systemic site would be even smaller. Theseembodiments are also attractive where the drug's biological activity issubstantially specific for the specific treatment site, and systemicdelivery of the drug to the patient would have no substantial,undesirable effect.

[0110] Where the drug's biological activity might have undesirablesystemic effects, the catheter preferably further comprises a wastereservoir for collection of drug that flows out of the delivery conduitthrough the diversion pathway. It may be desirable to maintain the wastereservoir at readily accessible site so that waste drug in the wastereservoir can be readily withdrawn, particularly where the subject is toreceive therapy for an extended period of time.

[0111] The amount of drug delivered to the treatment site is adjusted bymanipulation of one or more flow regulators of the drug delivery system.The method of altering an amount of drug administered to a treatmentsite according to the invention takes advantage of the fact thataltering the amount of drug that flows into the diversion pathway altersthe amount of drug that flows through the drug delivery outlet.Specifically, where the flow regulator is adjusted to increase theamount of drug that flows out the diversion pathway, the amount of drugdelivered through the delivery outlet to the treatment site isproportionately decreased. Likewise, where the flow regulator isadjusted to decrease the amount of drug that flows out the diversionpathway, the amount of drug delivered through the delivery outlet to thetreatment site is proportionately increased. For example, the flowregulator can provide for redirection (e.g., into or away from thediversion pathway) of about 0.5% up to 100%, usually about 5% to 90%,normally about 10% to 75% or about 25% to 50% of the drug flow in thedrug delivery pathway. The relative amount of drug diverted into thediversion pathway can be selected according to patient need, e.g.,developments of side-effects, responsiveness to therapy, etc.

[0112] The overall rate of drug delivery through the drug deliverypathway can be adjusted using the flow regulator in a variety of ways.The flow regulator can be set at relative degrees of opening and closingof the drug diversion pathway and drug delivery pathway. For example,the relative portions of drug flowing through the drug delivery pathwayand the diversion pathway can be 90:10, 80:20, 50:50, 25:75, etc.Alternatively, the rate of drug flow can be adjusted by varying theamount of time the drug delivery pathway is open relative to the amountof time the diversion pathway is open. For example, over a given timeinterval (e.g., seconds, minutes, hours), the ratio of time the drugdelivery pathway is open versus the time the diversion pathway is open(delivery:diversion) can be 10:1, 5:1, 3:1, 2:1, 0.5:1, etc.

[0113] The invention as shown and described is considered to be the oneof the most practical and preferred embodiments. It is recognized,however, that the departures may be made therefrom which are within thescope of the invention and that obvious modifications will occur to oneskilled in the art upon reading this disclosure.

What is claimed is:
 1. A method for delivering a desired amount of adrug to a treatment site of a subject, the method comprising: causing aquantity of drug to exit from a drug reservoir of a drug delivery devicein a direction toward a treatment site; and diverting a portion of thequantity of drug exiting the drug delivery device away from thetreatment site such that said diverted portion does not reach thetreatment site; wherein said diverting results in delivery of a desiredamount of drug to the treatment site.
 2. The method of claim 1, whereinthe treatment site is a biologically confined treatment site and thediverted drug is diverted into a systemic site within the subject. 3.The method of claim 1, wherein the diverted drug is collected into awaste reservoir.
 4. The method of claim 1, wherein the desired amount ofdrug is delivered to the treatment site by varying the amount of drugdelivered to the treatment site relative to the amount of drug divertedfrom the drug delivery device.
 5. The method of claim 1, wherein saiddiverting is by intermittent disruption of flow of drug exiting the drugdelivery device.
 6. A flow regulator (10) for regulating the flow of adrug from a drug delivery device (110) to a treatment site in the bodyof a subject, the flow regulator comprising: a proximal delivery inlet(21), wherein the proximal delivery inlet is proximal to andcommunicably attached to the drug delivery device; a distal deliveryoutlet (22), wherein the distal delivery outlet is distal to the drugdelivery device; a delivery conduit (20) extending between the proximaldelivery inlet and the distal delivery outlet, the delivery lumendefining a delivery pathway (60); and a diversion element (40)positioned so as to facilitate diversion of flow of the drug in adirection away from the distal delivery outlet.
 7. The flow regulator ofclaim 6, wherein the diversion element (40) is manually adjustable. 8.The flow regulator of claim 6, wherein the diversion element (40) isremotely adjustable.
 9. The flow regulator of claim 8, wherein thediversion element (40) is adjustable by use of a remote actuationdevice.
 10. The flow regulator of claim 6, wherein the diversion element(40) is a valve.
 11. The flow regulator of claim 10, wherein the valveis a compression valve for compressing against a deformable wall of thedelivery conduit (20) at a site distal to a proximal drug exit outlet(25).
 12. The flow regulator of claim 10, wherein the valve is arotatable valve (42).
 13. The flow regulator of claim 10, wherein thevalve is a solenoid (47).
 14. The flow regulator of claim 6, wherein theflow regulator further comprises: a diversion conduit (30) comprising adiversion inlet (31), a diversion outlet (32), and a diversion lumenextending between the diversion inlet and diversion outlet, thediversion conduit lumen defining a diversion pathway (70); wherein drugdiverted by the diversion element (40) flows into the diversion pathwaydefined by the diversion conduit.
 15. The flow regulator of claim 14,wherein the delivery conduit (20) and the diversion conduit (30)intersect in a substantially T-shaped configuration.
 16. The flowregulator of claim 14, wherein the delivery conduit (20) and thediversion conduit (30) intersect in a substantially Y-shapedconfiguration.
 17. The flow regulator of claim 14, wherein the deliveryconduit (20) and the diversion conduit (30) intersect in a substantiallyU-shaped configuration.
 18. The flow regulator of claim 14, wherein thediversion conduit (20) is in fluid communication with a waste reservoir(90) for receiving drug from the diversion outlet (32).
 19. The flowregulator of claim 18, wherein the waste reservoir comprises (90) aself-sealing septum.
 20. The flow regulator of claim 6, wherein thedelivery conduit (20) comprises an attachment element (130) forattaching a drug delivery (110) device for delivery of drug into theproximal delivery inlet (21).
 21. The flow regulator of claim 6, whereinthe delivery conduit (20) comprises a valve at a delivery conduit distalend.
 22. The flow regulator of claim 6, wherein the flow regulator (10)is contained within a housing element (45).
 23. The flow regulator ofclaim 14, wherein the housing element (45) comprises a biocompatible,implantable material.
 24. The flow regulator of claim 6, wherein theflow regulator (10) is attached to a drug delivery catheter (120) at adelivery conduit distal end to provide for flow of drug from thedelivery pathway (60), out the distal delivery outlet (22), and into alumen of the drug delivery catheter.
 25. The flow regulator of claim 9,wherein the remote actuation device comprises power source for actuationof the diversion element.
 26. The flow regulator of claim 9, wherein theflow regulator is programmable by the remote actuation device.
 27. Adrug delivery system (100) comprising; the flow regulator (10) of claim6; and a drug delivery device (110); wherein the drug delivery device isattached to the flow regulator to facilitate delivery of a drug from thedrug delivery device, through the delivery conduit (20) lumen, and outthe distal delivery outlet (22).
 28. The drug delivery system of claim27, wherein the flow regulator is detachably attached to the drugdelivery device (110).
 29. The drug delivery system of claim 27, whereinthe drug delivery device (110) is a convective drug delivery device. 30.The drug delivery system of claim 27, wherein the drug delivery device(110) is a diffusive drug delivery device.
 31. The drug delivery systemof claim 27, wherein the flow regulator further (110) comprises: adiversion conduit (30) comprising a diversion inlet (31), a diversionoutlet (32), and a diversion lumen extending between the diversion inletand diversion outlet, the diversion conduit lumen defining a diversionpathway (70); wherein drug diverted by the diversion element (40) flowsinto the diversion pathway defined by the diversion conduit.
 32. Thedrug delivery system of claim 27, wherein the drug delivery device (110)is implantable.
 33. The drug delivery system of claim 27, wherein thesystem further comprises a remote actuation device for actuation of thediversion element (40).
 34. A drug delivery catheter (120) comprising acatheter body defining a proximal opening, a distal opening, and acatheter lumen extending between the proximal and distal openings, thecatheter further comprising a flow regulator (10) according to claim 6,wherein the catheter lumen and the flow regulator delivery lumen are influid communication.
 35. The drug delivery catheter of claim 34, whereinthe flow regulator delivery conduit (20) is continuous and integral tothe catheter body.
 36. The drug delivery catheter of claim 34, whereinthe flow regulator (10) is positioned at a proximal portion of thecatheter.
 37. A method of administering drug to a treatment site in asubject, the method comprising: implanting at least the distal end ofthe flow regulator delivery conduit of the flow regulator of claim 1 ata treatment site within a subject; and delivering drug from a drugdelivery device, through the drug delivery pathway of the flowregulator, and to the treatment site; wherein the drug is administeredto the treatment site in the subject.
 38. The method of claim 37,wherein the delivery conduit lumen is suitable for delivery of the drugat a low volume rate.
 39. The method of claim 37, wherein the flowregulator drug delivery conduit provides for delivery of drug to atleast two treatment sites.
 40. The method of claim 37, wherein thetreatment site is subcutaneous, percutaneous, intravenous,intramuscular, intra-arterial, intravascular, intraperitoneal,intraspinal, epidural, intrathecal, intracranial, intracardial,peritumoral, or intratumoral.
 41. The method of claim 37, wherein thetreatment site is a site within a kidney, liver, pancreas, heart, lung,eye, ear, lymph node, breast, prostate, ovary, testicle, thyroid,spleen, central nervous system, skeletal muscle, bone, lymph vessel,artery, arteriole, capillary bed, blood vessel, vein, peripheral nervoussystem, digestive system, gastrointestinal tract, urinary bladder, gallbladder, adrenal gland, adipose tissue, parathyroid gland, uterus,fallopian tube, skin, tumorous growth, autologous graft, syntheticgraft, or site of microbial infection.
 42. A method of controlling anamount of drug administered to a treatment site in a subject, the methodcomprising: introducing a drug into the flow regulator proximal deliveryinlet of the drug delivery system of claim 1, said introducing resultingin drug flowing through the drug delivery pathway and to a treatmentsite in a subject at which a distal end of the drug delivery conduit isimplanted; and adjusting the diversion element of the flow regulator todivert drug from the drug delivery pathway; wherein said adjustingalters the amount of drug that is delivered to the treatment site in thesubject.
 43. The method of claim 42, wherein the drug delivery device isa constant rate drug delivery device.
 44. The method of claim 42, wheredrug diverted from the drug delivery pathway is delivered to the subjectsystemically.
 45. The method of claim 42, wherein the flow regulatorcomprises a waste reservoir for receiving drug diverted from thedelivery pathway.
 46. The method of claim 42, wherein the distal end ofthe drug delivery conduit is attached to a drug delivery catheter toprovide for extension of the drug delivery pathway to a catheterdelivery outlet at the catheter distal end, wherein at least thecatheter distal end is implanted at the treatment site.
 47. The methodof claim 46, wherein the catheter is adapted for delivery of drug to twotreatment sites.
 48. The method of claim 42, wherein the treatment siteis subcutaneous, percutaneous, intravenous, intrathecal, intramuscular,intra-arterial, intravascular, intraperitoneal, intraspinal, epidural,intracranial, intracardial, peritumoral, or intratumoral.
 49. The methodof claim 42, wherein the treatment site is a site within a kidney,liver, pancreas, heart, lung, eye, ear, lymph node, breast, prostate,ovary, testicle, thyroid, spleen, central nervous system, skeletalmuscle, bone, lymph vessel, artery, arteriole, capillary bed, bloodvessel, vein, peripheral nervous system, digestive system,gastrointestinal tract, urinary bladder, gall bladder, adrenal gland,adipose tissue, parathyroid gland, uterus, fallopian tube, skin,tumorous growth, autologous graft, synthetic graft, or site of microbialinfection.
 50. The method of claim 42, wherein the diversion element isadjusted for a first time period so as to facilitate flow through thedelivery conduit, and for a second time period so as to decrease flowthrough the diversion conduit, wherein varying the length of the firstand second time periods results in alteration in the amount of drugdelivery to the treatment site.
 51. The method of claim 42, wherein theflow regulator further comprises: a diversion conduit comprising adiversion inlet, a diversion outlet, and a diversion lumen extendingbetween the diversion inlet and diversion outlet, the diversion conduitlumen defining a diversion pathway; wherein drug diverted by thediversion element flows into the diversion pathway defined by thediversion conduit.
 52. The method of claim 51, wherein the diversionelement is adjusted so that the delivery conduit and the diversionconduit are each partially open.
 53. The flow regulator of claim 6,wherein at least the distal delivery outlet (22) is adapted forimplantation at the treatment site.
 54. The flow regulator of claim 53,wherein the diversion element (40) is adapted for implantation.
 55. Theflow regulator of claim 6, wherein the diversion element (40) isprovided to divert drug away from the distal delivery outlet (22) and toa systemic site within the subject.